Abstract
The T cell receptor (TCR) repertoire encodes immune exposure history through the dynamic formation of immunological memory. Statistical analysis of repertoire sequencing data has the potential to decode disease associations from large cohorts with measured phenotypes. However, the repertoire perturbation induced by a given immunological challenge is conditioned on genetic background via major histocompatibility complex (MHC) polymorphism. We explore associations between MHC alleles, immune exposures, and shared TCRs in a large human cohort. Using a previously published repertoire sequencing dataset augmented with high-resolution MHC genotyping, our analysis reveals rich structure: striking imprints of common pathogens, clusters of co-occurring TCRs that may represent markers of shared immune exposures, and substantial variations in TCR-MHC association strength across MHC loci. Guided by atomic contacts in solved TCR:peptide-MHC structures, we identify sequence covariation between TCR and MHC. These insights and our analysis framework lay the groundwork for further explorations into TCR diversity.
Highlights
T cells are the effectors of cell-mediated adaptive immunity in jawed vertebrates
We focus on statistical association of T cell receptor (TCR) occurrence with human leukocyte antigen (HLA) type, and show that many of the most highly HLA-associated TCRs are likely responsive to common pathogens: for example, eight of the ten TCRb chains most highly associated with the HLA-A*02:01 allele are likely responsive to one of two viral epitopes
Each feature—such as the presence of a given HLA allele (e.g. HLA-A*02:01) or CMV seropositivity— defines a subset of the cohort members positive for that feature, and can be encoded as a vector of 666 binary digits. This phenotype occurrence pattern of zeros and ones can be compared to the occurrence patterns of all the public TCRb chains to identify similar patterns, as quantified by a pvalue for significance of co-occurrence across the 666 subjects; thresholding on this p-value produces a subset of significantly associated TCRb chains whose collective occurrence in a repertoire was found by Emerson et al to be predictive of the feature of interest
Summary
T cells are the effectors of cell-mediated adaptive immunity in jawed vertebrates. To control a broad array of pathogens, massive genetic diversity in loci encoding the T cell receptor (TCR) is generated somatically throughout an individual’s life via a process called V(D)J recombination. All nucleated cells regularly process and present internal peptide antigens on cell surface molecules called major histocompatibility complex (MHC). Through the interface of TCR and MHC, a T cell with a TCR having affinity for a peptide antigen complexed with MHC (pMHC) is stimulated to initiate an immune response to an infected (or cancerous) cell. The responding T cell proliferates clonally, and its progeny inherit the same antigen-specific TCR, constituting long-term immunological memory of the antigen. The diverse population of TCR clones in an individual (the TCR repertoire) dynamically encodes a history of immunological challenges
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